title: The mechanism of sertraline-induced [Ca(2+) ](i) rise in human PC3 prostate cancer cells.
abstract: The effect of sertraline, an antidepressant, on cytosolic-free Ca(2+) levels ([Ca(2+) ](i) ) in human cancer cells is unclear. This study examined whether sertraline altered basal [Ca(2+) ](i) levels in suspended PC3 human prostate cancer cells by using fura-2 as a Ca(2+) -sensitive fluorescent probe. At concentrations of 10-150 μM, sertraline induced a [Ca(2+) ](i) rise in a concentration-dependent fashion. The Ca(2+) signal was reduced partly by removing extracellular Ca(2+) indicating that Ca(2+) entry and release both contributed to the [Ca(2+) ](i) rise. Sertraline induced Mn(2+) influx, leading to quench of fura-2 fluorescence suggesting Ca(2+) influx. This Ca(2+) influx was inhibited by the suppression of store-operated Ca(2+) channels or by the modulation of protein kinase C activity. In Ca(2+) -free medium, pre-treatment with the endoplasmic reticulum Ca(2+) pump inhibitor thapsigargin or 2,5-di-(t-butyl)-1,4-hydroquinone nearly abolished sertraline-induced Ca(2+) release. Conversely, pre-treatment with sertraline greatly reduced the inhibitor-induced [Ca(2+) ](i) rise, suggesting that sertraline released Ca(2+) from the endoplasmic reticulum. Inhibition of phospholipase C inhibited sertraline-induced [Ca(2+) ](i) rise. At 20-30 μM, sertraline killed cells in a concentration-dependent manner. The cytotoxic effect of sertraline was enhanced by chelating cytosolic Ca(2+) with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid/AM. Annexin V-FITC data suggest that sertraline (20 and 30 μM) evoked apoptosis in a concentration-dependent manner. Together, in PC3 human prostate cancer cells, sertraline induced [Ca(2+) ](i) rises by causing phospholipase C-dependent Ca(2+) release from the endoplasmic reticulum and via multiple Ca(2+) influx pathways that involve store-operated Ca(2+) channels. Sertraline also induced apoptosis that was not triggered by [Ca(2+) ](i) rise.
authors.affiliation: Department of Surgery, Kaohsiung Veterans General Hospital, Taiwan.
authors.forename: Jong-Khing
authors.initials: JK
authors.lastname: Huang
authors.forename: Hong-Tai
authors.initials: HT
authors.lastname: Chang
authors.forename: Chiang-Ting
authors.initials: CT
authors.lastname: Chou
authors.forename: Su-Shung
authors.initials: SS
authors.lastname: Shu
authors.forename: Chun-Chi
authors.initials: CC
authors.lastname: Kuo
authors.forename: Jeng-Yu
authors.initials: JY
authors.lastname: Tsai
authors.forename: Wei-Chuan
authors.initials: WC
authors.lastname: Liao
authors.forename: Jue-Long
authors.initials: JL
authors.lastname: Wang
authors.forename: Ko-Long
authors.initials: KL
authors.lastname: Lin
authors.forename: Yi-Chau
authors.initials: YC
authors.lastname: Lu
authors.forename: I-Shu
authors.initials: IS
authors.lastname: Chen
authors.forename: Shuih-Inn
authors.initials: SI
authors.lastname: Liu
authors.forename: Chin-Man
authors.initials: CM
authors.lastname: Ho
authors.forename: Chung-Ren
authors.initials: CR
authors.lastname: Jan
mesh_terms: D000928:Antidepressive Agents / Q000494:pharmacology*; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D008297:Male; D008345:Manganese / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D020280:Sertraline / Q000494:pharmacology*; D010738:Type C Phospholipases / Q000502:physiology
chemical_list: D000928:Antidepressive Agents; D008345:Manganese; D010738:Type C Phospholipases; D020280:Sertraline; D002118:Calcium